GAITHERSBURG, Md. -- Midway through a two-day FDA hearing on the safety of drug-eluting coronary stents the hard questions were still open.

GAITHERSBURG, Md., Dec. 8 -- Midway through a two-day FDA hearing on the safety of drug-eluting coronary stents the hard questions were still open.

The opening session saw the blue-ribbon FDA advisory panel agree on less contentious issues. The panel is attempting answer a series of eight questions put to it by the FDA on the future of coronary stents, and the more difficult issues were being faced today.

After considering testimony yesterday from drug-eluting stent-makers, the panel agreed that the large benefit of the devices outweighed the small risk of late-stent thrombosis. Late-stent thrombosis is the threat that has clouded the percutaneous coronary intervention world for the past few months.

But the panelists limited that opinion to stents used according to the narrow protocols set forth in the clinical trials conducted as part of the FDA-approval process. So that agreement represented a small part of the real clinical stent world where off-label use is common.

And, although the panel members generally agreed that extending use of Plavix (clopidogrel) in a dual antiplatelet regimen with aspirin was likely to reduce the risk of stent thrombosis, they decided against recommending changing labels of drug-eluting stents to require at least 12 months of dual antiplatelet therapy.

Today the panel is to face up to thornier questions dealing with two much-debated areas. These are risks associated with off-label use of drug-eluting stents and the issue of raising the bar for future FDA approvals of drug-eluting stents.

In back-to-back presentations representatives yesterday from Johnson & Johnson's Cordis, which makes Cypher, a sirolimus-eluting stent and Boston Scientific, which makes Taxus, a paclitaxel-eluting stent offered data on randomized clinical trials that confirmed that late-stent thrombosis is more likely to occur with both Cypher and Taxus than it is with a bare metal stent.

But, as panel member Eric Topol, M.D., of Scripps Health in San Diego repeatedly pointed out, "there is a disconnect between the thrombosis rate and the rate of death or myocardial infarction."

Dr. Topol said that disconnect was important because it suggested that the acknowledged increased risk of thrombosis was not clinically significant.

Both Campbell Rogers, M.D., chief technology officer at Cordis, and Donald S. Baim, M.D., executive vice president and chief medical officer at Boston Scientific, argued that the absence of difference in hard events was explained by the dramatic reduction in restenosis rates seen with both Cypher and Taxus stents.

Restenosis "is not a benign event," said Dr. Rogers, who noted that restenosis often presents as acute myocardial infarction, which pushes up the event rate for bare-metal stents in a way that balanced thrombotic events observed with drug-eluting stents.

When the panel was asked to vote on this question: "When used in accordance with their labeled indications, are [drug-eluting stents] associated with an increase risk of stent thrombosis, death, or myocardial infarction compared with bare metal stents?" the answer was yes and no.

A majority of panel members said that risk of stent thrombosis appeared to be greater for drug-eluting stents, but all panelists said there was no increased risk of death or myocardial infarction compared with bare-metal stents."

But as panel member Steven Nissen, M.D., of the Cleveland Clinic pointed out, the disconnect between thrombosis and events was "extended only so far as the clinical trial data presented."

He noted that clinical trial data are distinct from the population represented by "labeled indications," because outcomes are typically better in the closely monitored, highly motivated world of clinical trials.

So the take home message from the panel was that in the real world the risks of drug-eluting stents may not outweigh the benefits.

The panel agreed that current labeling for drug-eluting stents could remain basically unchanged, although a majority favored adding information about antiplatelet therapy recommendations contained in the latest joint guidelines from the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions.

The ACC/AHA/SCAI recommendation is for 12 months of dual antiplatelet therapy (aspirin plus Plavix [clopidogrel]), which the panel said should be mentioned in the label information, but the panelists shied away from changing the label to require at least 12 months of Plavix. Yet when panel chairman William H. Maisel, M.D., M.P.H., of Harvard polled the members about their own personal preference, each said they would take Plavix for at least 12 months if they had a drug eluting stent in their own hearts.

As the day wore on, the panel members heard results of registry data that presented what many claimed was a "real-world" picture of drug-eluting stents.

In those registry data, the drug-eluting stents were consistently associated with a higher thrombosis rate than bare-metal stents, but industry representatives argued that comparing drug-eluting stents and bare-metal stents in these real world settings is an unfair comparison.

The patients treated with drug-eluting stents have more severe disease characterized by complicated lesions, small vessels, or comorbidities such as diabetes. These patients, Boston Scientific's Dr. Bain said, "wouldn't be treated with bare metal stents -- they would go to surgery."

To that end Dr. Bain reported Taxus registry data using what he said where historical coronary artery bypass graft data as a comparator.

But in his comparison, he reported that CABG carried a mortality rate of 6.5%, which was significantly higher than the rate for Taxus, but this comparison raised the ire of panel member Norman S. Kato, M.D., a cariodiothoracic surgeon from Cardiac Care Medical Group in Encino, Calif., who pointedly told Dr. Bain that this "CABG mortality is nowhere near 6.5%."

In an interview following the day's session, Dr. Kato said a more accurate mortality rate for CABG would be just over 2%.

Drug-eluting stents have dominated the percutaneous coronary intervention arena since 2003 when Cypher won FDA approval, followed a year later by Taxus.

But it is only in the past several months that the meteoric assent of these devices has slowed as serious concerns about their safety have been raised.

It began last March when a team of interventional cardiologists from Basel, Switzerland, reported that drug-eluting stents had a significantly higher rate of late stent thrombosis -- an event that is often fatal -- than bare-metal stents. Since then, the drug-eluting stents have come under renewed scrutiny.

The debate reached a flashpoint in September at the European Society of Cardiology/World Cardiology Congress in Barcelona. At that meeting, a pair of meta-analyses, as well as data from two registries all reported increased late stent thrombosis with drug eluting stents.

These data were bolstered by 18-month data from the same Swiss investigators who had originally raised the warning flag. The Swiss suggested that the risk increased at 12 months and continued in a linear fashion up to 18 months.

Within days of the close of the Barcelona meeting, the FDA announced plans for this week's safety hearing.

In October, the drug-eluting stent controversy dominated every day of the week-long Transcathter Therapeutics meeting in Washington.

At the American Heart Association meeting last month, the issue was again a headliner at plenary sessions as well as hot topic debates.

The findings in those reports varied widely from increased risk of stent thrombosis ranging from 0.03% to 0.06% per year to studies that reported no increased risk of stent thrombosis for drug-eluting stents.

Just this week, two studies -- one in the Journal of the American College of Cardiology and the other in the Journal of the American Medical Association -- reported that risk of events increased when treatment with Plavix was stopped.

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